Project Summary Binge drinking has significant negative consequences for health and society, and is a major predictor for the development of an alcohol use disorder (AUD). The High Drinking in the Dark (HDID-1) line of mice, selectively bred for high blood ethanol concentrations (BECs) in a limited access binge-like drinking task, exhibit differential gene expression of a number of glucocorticoid receptor (GR) regulator proteins relative to their low- drinking founder line, HS/Npt. GR expression has been shown to be altered in response to chronic alcohol exposure and to promote further alcohol intake in dependence-like models, but GR dysregulation has not yet been identified as a genetic risk factor for excessive alcohol consumption in non-dependent animals. Preliminary data show that HDID-1 mice exhibit a dose-dependent reduction in binge drinking when given mifepristone, a GR antagonist, after only being exposed to a single 2-hour ethanol drinking session. These data suggest that selection for high BECs in the HDID-1 line has led to a sensitized GR system that may promote binge drinking. The goal of this fellowship project is to investigate the role of enhanced GR activity as a genetic risk factor for excessive alcohol consumption. Aim 1 will characterize GR expression and transcriptional activity in the brains of the high-drinking HDID-1 mice relative to the low-drinking founder line, HS/Npt. Specifically, GR and GR-related signaling genes in the nucleus accumbens (NAc) will be quantified, as GR expression in the NAc has previously been shown to promote alcohol intake. Aim 2 will determine whether pharmacological manipulation of GR in the NAc can bi-directionally modulate binge drinking. Bilateral cannulation will be performed in the NAc of (1) HDID-1 mice to deliver a GR antagonist and attempt to reduce binge drinking, and of (2) HS/Npt mice to deliver a GR agonist and attempt to increase binge drinking. The results of this aim will determine whether GR manipulation in the NAc is sufficient to alter binge drinking. Aim 3 will investigate whether GR antagonism in HDID-1 mice is sufficient to prevent escalated drinking after chronic intermittent ethanol (CIE) vapor exposure, a model of relapse-like drinking. The results of this aim will determine whether the same mechanisms driving binge drinking in HDID-1 mice also underlie relapse-like drinking. Aim 1 utilizes a basic science approach to examine molecular pathways that may have been altered through selection pressure, while Aims 2 and 3 will provide translational insight into potential pharmacological treatments for patients with AUD. Together, the experiments in this project will provide a better understanding of how GR activity in the brain contributes to excessive alcohol consumption in both non-dependent and dependent-like models of drinking.